A central issue in cancer chemotherapy is the severe toxic side effects of anticancer agents on healthy tissues, which invariably imposes dose reduction, treatment delay or even discontinuance of therapy (Fennelly (1995) Clin. Cancer Res. 1:575-582; Hanjani, et al. (2002) Gynecol. Oncol. 85:278-284; Kobayashi, et al. (2002) Chronobiol. Int. 19:237-251; Ross and Small (2002) J. Urol. 167:1952-1956; Markman, et al. (2002) J. Clin. Oncol. 20:2365-2369; Sehouli, et al. (2002) Gynecol. Oncol. 85:321-326). Cytotoxicity for healthy organs can be significantly diminished by employing a drug delivery system which targets cancer cells (Alvarez, et al. (2002) Expert. Opin. Biol. Ther. 2:409-417; Dass and Su (2001) Drug Deliv. 8:191-213; Kopecek, et al. (2001) J. Controlled Rel. 74:147-158; Kunath, et al. (2000) Eur. J. Pharm. Biopharm. 49:11-15; Minko, et al. (2001) Dis. Manag. Clin. Outcomes 3:48-54; Vasey, et al. (2002) J. Clin. Oncol. 20:1562-1569). The usage of these drug delivery systems prevents, in most cases, the uptake of the drug by normal cells and enhances the influx and retention of the drug in cancer cells.
NSCLC remains one of the leading causes of cancer-related mortality worldwide. NSCLC represents a heterogeneous group of diseases that are often classified together due to similarities in diagnosis, prognosis and treatment. The standard-of-care with an anticancer agent paclitaxel and a platinum drug extends life only minimally due to drug-related toxicities, poor treatment/prevention of metastases, and resistance. Increasing drug doses in order to boost tissue concentrations is not feasible due to cytotoxic effects and low solubility.
The lung is the only organ in the body that accepts the entire venous blood output from the heart. Since it is the first capillary bed encountered by the venous blood, it is in a singular position to entrap a wide variety of particles. “Passive” drug targeting to the lung (i.e., accumulation) can be achieved by taking advantage of this natural flow-filtration phenomenon. In 1964, human serum albumin “macroaggregates” (“MAA”) exhibiting suitable size and degradation properties became the first MPs approved for IV injection and lung targeting. Two approved products remain on the market today as pulmonary perfusion diagnostic agents, Pulmolite® (CIS-US) and Draximage® (Draxis). There are not any products for delivering drugs to the lung that exploit this established and safe pathway. The rationale for passive lung accumulation is compelling—MAA product and MPs are efficiently entrapped (>90%) after a single injection as compared to only 5-20% of an inhaled dose. In addition, inhalers must be used multiple times daily but a single IV injection may provide effective treatment for up to one week. Size and deformability are the two major determinants of the passive accumulation and retention of MPs in the lung.
In addition to these factors, toxicity is also influenced by the total particle dose. Presently, approved human MAA dosages are much lower (<0.2 mg or ˜350,000 MPs) than the corresponding LD50 in animals (43.8 mg/kg to 82.6 mg/kg) suggesting that tolerable human MP doses may be significantly higher than what is currently used in the diagnostic product. It has been estimated that only ˜0.6% of available (i.e., opened) capillary vessels are occluded immediately following administration of 1×106 albumin aggregates (4 times the current human MAA dose). About 33% of all pulmonary capillaries are normally collapsed and not available (the main reason for this is that lung blood pressure is about ⅙ of systemic blood pressure). When micro-occlusions occur, collapsed capillaries are recruited in order to maintain normal physiological perfusion conditions. Therefore, the maximum tolerated dose of MPs in humans is higher than current MAA doses and in the milligram range.
While targeted drug delivery is an effective approach for improving drug concentrations, the options for lung targeting are narrow. The inherently low absorption and poor lung distribution associated with inhalation are further diminished as a result of reduced lung function in NSCLC patients. Despite recent advances in molecular characterization and targeted and adjuvant therapies, surgical resection remains the mainstay of curative treatment. Unfortunately, less than one third of NSCLC patients present with resectable disease. Neoadjuvant chemotherapy alone or with concurrent radiation is often used for stage IIIA NSCLC but is often tried in patients with stage IIIB and at times in patients with stage I or II disease. The general prognosis of NSCLC patients remains poor and unpredictable due to the high invasiveness potential of the disease. However, after the initial diagnosis, more than half of the patients with localized lung cancer survive at least 5 years. Therefore, an alternative delivery approach that targets primary lung tumors and controls metastasis is urgently needed.